Solid bodies containing active substances and a structure consisting of hydrophilic macromolecules, plus a method of producing such bodies

ABSTRACT

The invention relates to accurately meterable shaped articles, for example granules or pellets, containing hydrophilic macromolecules, active compounds and optionally further pharmaceutically acceptable structure-forming substances and auxiliaries, the active compound being present in a matrix in dissolved, suspended or emulsified form, and a novel process for the production of these shaped articles, the process being particularly economically and ecologically acceptable, and use of the shaped articles as medicaments, in which the bioavailability, shelf life and tolerability is increased. Using the shaped articles or mixtures according to the invention, intermediates or final products for pharmacy, cosmetics, diagnosis, analysis or dietetics (healthcare) can additionally be advantageously prepared.

This application is a 371 of PCT/DE93/00038 filed Jan. 18, 1993.

The invention relates to accurately meterable powders, granules orpellets comprising hydrophilic macromolecules, active compounds andoptionally other pharmaceutically acceptable structure-formingsubstances and auxiliaries, the active compound being dissolved,suspended or emulsified in a matrix, and a novel process for theproduction of these powders, granules or pellets, and furthermore theiruse as a medicament, cosmetic, diagnostic or dietetic foodstuff(healthcare). Active compounds employed are preferably dihydropyridinederivatives, in particular nifedipine, nitrendipine or nisoldipine.

Granules or pellets as shaped articles serve in the pharmaceuticalindustry mainly as intermediates for tableting. Shaping here should leadto a free-flowing, granular and dust-free product which, on account ofits homogeneity, improves technological processing and dosage accuracy.Moreover, pellets, as a modern multiple-unit pharmaceutical form, forexample filled into hard gelatin capsules, possess a number ofadvantages compared with single-unit pharmaceutical forms, such as e.g.tablets or coated tablets:

They disperse uniformly in the gastrointestinal tract.

On account of their small size shorter gastric residence times result incontrast to monolithic pharmaceutical forms, especially with entericallycoated pharmaceutical forms.

As individual aggregates they dissolve more rapidly in thegastrointestinal tract in contrast to a compressed tablet, which mustfirst disintegrate into its granule particles.

Pellets with differing release of active compound can be individuallymetered in mixed form.

However, the fundamental problem of the necessary shaping ofpulverulent-crystalline active compounds and auxiliaries to processablegranules (pellets) as shaped articles underlies all processes of theprior art.

A distinction is made here between building up and breaking downprocesses. It is common to all processes that until now granules orpellets as shaped articles were only obtained via various andcomplicated partial steps.

In the breaking down processes--presented in simplified form--thepharmaceutical substances and auxiliaries are first comminuted, broughtto a uniform grain size by sieving and then mixed. Dry or moistgranulation then takes place, in which the powder mixture is aggregatedand then comminuted to give grains of granular material. In the nextstep, if necessary, it is dried and sieved again.

In the case of the building-up granules, grains of granular material areformed from the powdered pharmaceutical substances and auxiliaries withcontinuous addition of granulation fluid with simultaneous drying in acontrolled process (e.g. fluidized bed process).

By means of subsequent, special rounding processes (e.g. Marumerizer®),round, bead-shaped granule particles (pellets) are obtained. Adisadvantage in this case is that in the rounding of already prepared,unshaped granule particles substance matter containing pharmaceuticalsubstance is lost and cannot be directly fed to the granulation processagain. This is certainly a problem in terms of cost and disposal. At thesame time, the mechanical shaping leads to a non-uniform product.

Special pelleting techniques are, for example, build-up dry pelleting bycompaction and fluidized bed granulation, which produce veryunsatisfactory results with respect to shape and mechanical strength ofthe pellets.

All these preparation processes are technologically complicatedmulti-step processes. They are characterized by a multiplicity ofprocess parameters of technological type, such as e.g. temperature,moisture content, homogeneity of the mixtures etc.

Furthermore, in all granulation and pelleting processes the use of awhole series of auxiliaries is necessary. Thus, for example, binders orgranulation fluids must be employed to bring the powdered material intoa solid, compact and processable form. The most accurate knowledge aboutthe physicochemical behavior e.g. heat of solution, solubility orcrystal formation tendency and great experience in working with thesesubstances is necessary to be able to assess the interaction of theseauxiliaries with one another and with the pharmaceutical substance incombination with all process parameters to be taken into account.

Thus the pharmaceutical requirements of granules (pellets) can oftenonly be fulfilled by empirical tests depending on the pharmaceuticalsubstance being processed and the administration form being formulatedtherefrom.

It is therefore understandable that the adherence to constant productionconditions during the complicated process is very difficult. It is thusnot possible, owing to the multiplicity of parameters to be taken intoaccount, to find a suitable process for every pharmaceutical substancein the case of the known production processes despite a high outlay ondevelopment and optimization.

If pellets or granules prepared according to the prior art are moreoverconsidered from biopharmaceutical aspects, it can be seen that thepharmaceutical substance from these aggregated shaped articles can bemade available to the body only after deaggregation and subsequentrelease. The multiplicity of adhesive and binding forces, which differin principle, in granules illustrates this problem. As a result ofhardening binders during drying (moist granulation) or as a result ofsintering or melt adhesion under action of pressure (dry granulation)solid bridges form whose binding forces in the body must be overcomefirst in order to release the pharmaceutical substance from thepharmaceutical form at all.

Each preparation step in the processes of the prior art can thus have anunfavorable effect on the release of the active compound and thus on itsbioavailability.

Looked at pharmacologically, dihydropyridine derivatives are amongst thecalcium antagonists. They are indicated in a number of cardiovasculardisorders, such as e.g. coronary heart disease, arterial hypertension,angina pectoris etc. The prescription frequency of about 700 milliondefined daily doses in 1989 very clearly confirms the market position ofthis substance group. The first representative of this group ofdihydropyridine derivatives, nifedipine (dimethyl1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate,C₁₇ H₁₈ N₂ O₆) was supplemented in the meantime by a number of potentderivatives, the so-called "second-generation dihydropyridines",particularly nitrendipine, ethyl methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate,C₁₈ H₂₀ N₂ O₆ and nisoldipine, isobutyl methyl1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate,C₂₀ H₂₄ N₂ O₆.

The dosage of commercially available nifedipine immediate-effectmedicaments when given in a single dose is customarily 5-10 mg; morerecent dihydropyridine derivatives are in some cases given at a lowerdose.

In order to bring dihydropyridines, particularly nifedipine, into anadministration form which releases the active compound sufficientlyrapidly in the body, pharmaceutical formulation developments havefrequently been proposed. These, however, are all compromises, becauseon the one hand the poor solubility or insolubility of these activecompounds in the physiological medium restricts or makes difficult theirrapid release from pharmaceutical forms. On the other hand, the rapidrelease, however, is a prerequisite for an onset of action afteradministration which is as rapid as possible. These processes are notunimportant for increasing patient compliance.

Conventional, technological methods in the preparation ofimmediate-effect pharmaceutical forms of dihydropyridine derivatives,particularly nifedipine, are the following:

a) processing of the active compounds with solubilizers (surfactants)and additionally

b) dissolution of the active compounds in organic solvents, e.g.polyether alcohols of tetrahydrofurfuryl alcohol.

Because of the known light sensitivity of the dihydropyridines, aconventional, colored soft gelatin capsule may be used e.g. as a carrier(light protection) for an abovementioned nifedipine solubilizate or anifedipine solution in an organic solvent. After administration, thenifedipine should be released from the pharmaceutical form in fine form.It is to be considered here, however, that the active compound is thennot actually free, but must first be released from its complex with thesolubilizer, with the disadvantage that it is not sufficiently rapidlyavailable to the body. Additionally, there is also always the risk inthis process that nifedipine precipitates under physiological conditionsin relatively coarse crystalline form as soon as the solubilizer(surfactant) is no longer active. Moreover, the use of surfactants ororganic solvents is not completely safe from toxicologicalconsiderations.

Liquid nifedipine preparations able to form drops are also commerciallyavailable. For the patient, these nifedipine drops are a very popularadministration form, particularly for elderly patients who find theswallowing of solid shaped articles (tablets, capsules) unpleasant orhave difficulties with it. Moreover, they have the advantage of goodmeterability.

Although liquid pharmaceutical preparations, looked at technologically,are actually well conceived immediate-effect pharmaceutical forms (theprocess of the disintegration of solid, "single-unit" forms such as, forexample, tablets or capsules does not apply), these preparations are notin keeping with the times in the case of the dihydropyridines on the onehand for the reasons already mentioned above (use of surfactants and/ororganic solvents), and on the other hand for a further, even morefar-reaching reason which is to be sought in this class of activecompound itself. As is known, dihydropyridines are highlylight-sensitive and tend to decompose, in particular in solutions.

Partial decomposition of the nifedipine as a result of admission oflight, even before taking, is therefore never to be excludedparticularly during withdrawal of nifedipine drops from the storagecontainer by the patient. Since this form of administration,particularly in the case of elderly patients, is a very time-consumingprocess, the risk of decomposition of active compound before actualadministration is thus additionally increased.

It is further to be taken into consideration that even the storage ofnifedipine drop solutions in brown or dark-colored glass bottles may notoffer adequate, relatively long storage stability (protection fromadmission of light|).

For dihydropyridine derivatives administration as an immediate-effectform having a rapid influx, the preparation itself being an activecompound solution, is desirable or advantageous from pharmacologicalconsiderations. However, owing to the physicochemical properties of theactive compound, such as, for example, inadequate water solubility,light sensitivity in solution etc., this administration form cannot berealized technologically or can only be realized in a roundabout manner.

The present invention has the object of proposing novel solids, aprocess for their production, and mixtures which on the one hand onaccount of their structure and composition improve the bioavailabilityand tolerability of pharmaceutical substances, are stable on storage,accurately meterable and present as a single or multiple unit and on theother hand can be prepared in an environmentally protective, simple andeconomical manner, process the active compounds in a gentle manner andthus, looked at all together, overcome the disadvantages of the priorart.

The present invention is in particular based on the object of providinga medicament for oral administration of dihydropyridine derivatives,particularly nifedipine, which is suitable for rapid pharmaceuticalsubstance release and overcomes the problems of the prior art.

This object is achieved according to the invention by activecompound-containing solids which comprise the pharmaceutical substancein dissolved, emulsified or suspended form in a solid or semisolidmatrix which mainly contains hydrophilic macromolecules of naturalorigin as structure-forming agents.

The hydrophilic macromolecules employed are: collagen, gelatin,fractionated gelatin, collagenhydrolyzates, gelatin derivatives, plantproteins, plant protein hydrolyzates, elastin hydrolyzates andcombinations of the abovementioned substances with one another.

In particular, the present invention makes available activecompound-containing solids which comprise a dispersion of at least oneactive compound or active compound mixture in a matrix which essentiallyincludes a structure-forming agent comprising hydrophilic macromoleculesselected from the group consisting of: collagen, gelatin, fractionatedgelatin, collagen hydrolyzates, gelatin derivatives, plant proteins,plant protein hydrolyzates, elastin hydrolyzates and mixtures of theabovementioned substances.

This object is further achieved by a process for the production ofactive compound-containing solids which comprises dissolving,emulsifying or suspending the active compound in a solution of thehydrophilic macromolecule (structure-forming agent) and shaping to giveshaped articles.

The solids can be dried if required.

In particular, the present invention makes available a process for theproduction of solids containing at least one active compound, whichcomprises

a) dissolving a structure-forming agent comprising hydrophilicmacromolecules selected from the group consisting of:

collagen, gelatin, fractionated gelatin, collagen hydrolyzates, gelatinderivatives, plant proteins, plant protein hydrolyzates and elastinhydrolyzates in an aqueous and/or organic solvent,

b) dispersing the active compound,

c) adding the mixture of dissolved structure-forming agent and dispersedactive compound obtained dropwise to a deep-cooled liquid and thusshaping the solid.

Solid within the meaning of the invention is understood as meaning onewhich is selected from the group consisting of:

powders, granules, pellets and micropellets in essentially symmetricallybuilt-up aggregates.

According to the invention, uniformly round solids, in particularpellets, are particularly suitable for pharmaceutical applications, theterm pellet preferably comprising a grain size range from about 0.2 to12 mm.

In the description of the invention the properties, preparation and useare preferably presented with the aid of round pellets.

However, the person skilled in the art can also employ other solids fromthe group consisting of: powders, granules, essentially symmetricallybuilt-up aggregates, advantageously for the production, in particular,of pharmaceutical forms.

In addition, the object of the present invention is achieved by amixture which contains at least one active compound and astructure-forming agent wherein the structure-forming agent is ahydrophilic macromolecule selected from the group consisting of:

collagen, gelatin, fractionated gelatin, gelatin derivatives, collagenhydrolyzates, plant proteins, plant protein hydrolyzates, elastinhydrolyzates, albumins, agar-agar, gum arabic, pectins, tragacanth,xanthan, natural and modified starches, dextrans, dextrins,maltodextrin, chitosan, alginates, cellulose derivatives, polyvinylalcohol, polyvinylpyrrolidone, polyacrylic acid and polymers ofmethacrylic acid and methacrylic acid esters; and their mixtures.

The active compound used according to the present invention ispreferably a dihydropyridine derivative, in particular nifedipine,nitrendipine or nisoldipine.

Preferred embodiments of the invention are described and claimed in thedependent claims.

The solid to semisolid or gelatinous pellets according to the inventionare round, uniform shaped articles in the range from 0.2-12 mm. Pelletsin the range from 0.2-2 mm are suitable for multiple unit dosage forms,pellets in the range from 2-12 mm can be used as a single unit dosageform.

With respect to medicament safety, exact dosage accuracy, homogeneity,tolerability and storage stability of the corresponding pharmaceuticalform are required by the pharmaceutical industry. With conventionalmedicament production, this standard is often only to be achieved with ahigh and cost-intensive outlay. The uniform grain size distribution ofthe claimed pellets, combined with a homogeneous dispersion of thepharmaceutical substance, improves the dosage accuracy distinctlycompared with the prior art. Furthermore, the active compounds embeddedin the pellet matrix are brought into a storage-stable form which has ahigh mechanical strength with low friability. Sensitive active compoundsare additionally reliably protected from external effects.

As shaped articles, the pellets according to the invention, which aredistinguished by their homogeneous round and uniform shape, are visuallyvery attractive on account of their harmonic total impression and canincrease acceptance in the patient. By means of appropriate coloring,the pellets, which appear clearly transparent and lustrous, opaque totransparent or nontransparent, can be developed to give unmistakablepharmaceutical specialties.

As a result of the advantageous protective colloid function of theclaimed macromolecules and the simultaneous embedding of the activecompounds in the polymeric matrix structure, the tolerability isdistinctly increased, in particular in the case of mucousmembrane-irritating active compounds. Thus e.g. the irritation of thegastric mucous membrane by acetylsalicylic acid can be effectivelydecreased by the mucous membrane-protective action of the claimedmacromolecules (cf. Example 7). As a pharmaceutical form, the pelletsdescribed are palatable and easy to take orally.

Surprisingly, the release of the active agent takes place in the bodywithout an advance disintegration process in all pharmaceuticalsubstances independently of whether they are dissolved, suspended oremulsified in the pellets according to the invention as shaped articles,in contrast to conventional granules, pellets or tablets. Inconventional preparations, the adhesive and binding forces which makepossible shaping at all must initially be overcome, in addition thesubaggregates thus obtained must be wetted and dissolved until thepharmaceutical substance is finally in an absorbable form. Depending onthe nature of the auxiliaries used and the preparation process used,conventional solid pharmaceutical forms can reduce the bioavailabilityof active compounds significantly.

The dissolution process from the pharmaceutical form as atime-determining factor depends in the case of the pellets according tothe invention as shaped articles exclusively on the nature andcomposition of the hydrophilic matrix system and can be modulated in therelease rate. Immediate-effect forms which dissolve within a few secondscan thus be formulated even as sustained-release forms. The dissolutionof the structure-forming agent is the rate-determining step.

In the case of hydrophobic or poorly soluble pharmaceutical substances,the hydrophilic macromolecules described improve the absorption or thebioavailability and can be coordinated according to the invention withthe particular pharmaceutical substance with respect to physicochemicaland pharmaceutical properties.

In the case of pharmaceutical substances which under conventionalconditions count as being poorly absorbable or having problematicbioavailability, a bioavailability increase of up to 100 to 150% canthus be achieved by incorporation, even as a simple dispersion, into apreparation according to the invention, in comparison with aconventional preparation of the same dose of the pharmaceuticalsubstance.

Obviously, the presence in a preparation according to the invention thusleads to a greatly increased (more effective) absorption of thepharmaceutical substance dose under physiological conditions.

The pharmaceutical substance-containing pellets are exposed during thegentle preparation process (shaping) to low temperatures and only comeinto contact with an inert medium (liquid nitrogen). Alteration of thepharmaceutical substances or contamination with residues of cooling oilsor organic solvents, such as is known, for example, of the classicalsoft gelatin capsule preparation, therefore does not take place.

From technological and biopharmaceutical aspects, the pellets describedin principle fulfill all requirements which are to be made of thisdosage form:

they are uniform in shape and color,

possess a narrow grain size distribution,

can be easily metered and filled,

have a high mechanical strength and shelf life,

release the pharmaceutical substance rapidly or in a modulated manner.

Within the meaning of the invention--on their own or inmixtures--hydrophilic macromolecules from the group consisting of:

collagen, gelatin, fractionated gelatin, gelatin derivatives, collagenhydrolyzates, plant proteins, plant protein hydrolyzates and elastinhydrolyzates can be employed.

These biogenic substances are pharmaceutically acceptable and non-toxic.The matrix properties of said proteins can be adjusted within widelimits with accurate knowledge of their physicochemical behavior andthus lead to a medicament in which the respective active compound ispresent in optimum and reproducible form.

Gelatin is a scleroprotein obtained from collagen-containing material,which has different properties depending on the preparation process. Itconsists essentially of four molecular weight fractions which affect thephysicochemical properties as a function of molecular weight andpercentage weight content. The higher e.g. the content of microgel (10⁷to 10⁸ D), the higher also the viscosity of the aqueous solution.Commercially available types contain up to 10 percent by weight. Thefractions of alpha-gelatin and its oligomers (9.5×10⁴ /10⁵ to 10⁶ D) arecrucial for the gel solidity and are customarily between 10 and 40percent by weight. Molecular weights below that of alpha-gelatin aredesignated as peptides and can amount to up to 80 percent by weight inconventional grades of gelatin (low-Bloom).

Gelatin possesses a temperature- and concentration-dependent reversiblesol/gel conversion behavior which is dependent on the molecularcomposition. As a measure of the gel formation power of the gelatin, itis internationally customary to give the Bloom number. Low commerciallyavailable grades start at 50 Bloom, high-Bloom types are about 300Bloom.

The chemical and physical properties vary depending on the preparationprocess, particularly gently obtained types of gelatin (low content ofdextrorotatory amino acids and peptides) having short sol/gel conversionrates and melting points above 37° C. (measured as a 10% strengthsolution).

Fractionated gelatin represents the special case of gelatin and isobtained from conventional gelatin by special preparation techniques,such as e.g. ultrafiltration. The composition can be varied e.g. byremoval of peptides (MW<9.5×10⁴ D) or by mixtures of individualfractions such as e.g. alpha chains, dimeric and trimeric chains ormicrogel.

Moreover, gelatin or fractionated gelatin has good surfactant propertieswith protective colloid action and emulsifying properties.

Collagen in native form is water-insoluble. By means of specialpreparation processes there are today soluble types of collagen havingan average molecular weight of about 300,000 D.

Gelatin derivatives are chemically modified gelatins, such as e.g.succinylated gelatin, which are used e.g. for plasma expanders.

Collagen hydrolyzate is understood as meaning a product obtained fromcollagen or gelatin by pressure hydrolysis or enzymatically which nolonger has sol/gel conversion power. Collagen hydrolyzates are readilycold water-soluble and the molecular weight composition can be between afew hundred D to below 9.5×10⁴ D. Products obtained by enzymatic routesare more homogeneous in molecular composition and additionally exhibitgood surfactant and emulsifier action.

The plant proteins and their hydrolyzates are newly developed products,which largely correspond to the collagen hydrolyzates in theirproperties. They are preferably obtained from wheat and soybeans andpossess, for example, molecular weights of about 200,000-300,000 D andabout 1,000-10,000 D respectively.

Elastin hydrolyzates are obtained enzymatically from elastin and consistof a single polypeptide chain. On account of their high content ofnon-polar amino acids they can be used in lipophilic systems. Elastinhydrolyzates have a molecular weight of about 2,000-3,000 D and havegreat film-forming power on the skin.

When using vegetable proteins, plant protein hydrolyzates, elastinhydrolyzates, or collagen hydrolyzates (cold water-soluble gelatins) orgelatins having a maximum in the molecular weight distribution of a fewhundred D to below 10⁵ D (variant A), the excipient material of theclaimed shaped articles after lyophilization carried out in a preferredembodiment of the invention surprisingly forms a highly porous and atthe same time mechanically stable matrix which dissolves rapidly andcompletely in cold water.

If the pharmaceutical substance is present in the matrix in dissolved orsuspended form, all said hydrophilic macromolecules in the indicatedmolecular weight ranges are suitable according to the invention on theirown or in mixtures. Emulsified pharmaceutical substances having rapidrelease are advantageously prepared by use of collagen hydrolyzates withstill present surfactant and emulsifier properties. Enzymaticallyobtained hydrolyzates which have a molecular weight between about 15,000and 20,000 D are particularly suitable.

The rapid dissolution of the matrix recipes described is suitable forpharmaceutical immediate-effect forms in which the active compound canbe present in a single or multiple dose.

For internal administration, instant preparations can advantageously beformulated from the pellets according to the invention as shapedarticles. If e.g. the active compound is embedded in a rapidlydissolving matrix and pelletized, storage-stable pellets are obtainedwhich (e.g. filled into a sachet) can be dissolved completely in coldwater within a few seconds.

According to the invention, hydrophilic macromolecules withsol/gel-forming properties such as e.g. gelatin and fractionatedgelatin, which possess a maximum in the molecular weight distributionabove 10⁵ D, may also be suitable as structure-forming substances.

If the pharmaceutical substance is present in dissolved, suspended oremulsified form in a sol/gel-forming structural matrix (variant B) suchas gelatin or fractionated gelatin, pellets are obtained which releasethe active compound--depending on the molecular composition of the typeof gelatin used--rapidly or slowly in aqueous medium at 37° C.

In a further embodiment of the invention, additions of plasticizers of1-50% (relative to the material to be processed) selected from the groupconsisting of: glycerol, propylene glycol, polyethylene glycols,triacetin, sorbitol, sorbitan mixtures, sorbitol solutions, glucosesyrup and other polyols or sugar alcohols, may be suitable. Saidsubstances affect the matrix according to the invention with respect toconsistency from solid to semisolid or gelatinous, its dissolutionbehavior and the viscosity. A particularly advantageously suitableplasticizer is sorbitol, which as a sweetener with non-cariogenicproperties simultaneously serves as a flavor correctant.

In a particular embodiment of the invention, pellets comprising matrixmaterials with plasticizer additions of 20 to 50% (relative to thematerial to be processed) have pronounced bioadhesive properties.

Furthermore, it may be desirable to add to the described matrixmaterials lipophilic constituents, such as e.g. phospholipids for theformation of liposomes.

For pellets as shaped articles which dissolve in water at 37° C. withina few minutes, types of gelatin are preferably selected whose peptidecontent is above 30% and which have a maximum in the molecular weightdistribution at about 10⁵ D to 10⁶ D.

For the formulation of pellets having properties which delay release,types of gelatin having a peptide content of below 10% and a microgelcontent of 10-15% are suitable within the meaning of the invention.Matrix materials or mixtures built up in this way possess a meltingrange from 35° C. to 40° C., preferably above 37° C., in aqueoussolution. Addition of plasticizers may be in the range between 1 and 30%(relative to the material to be processed).

The following can be employed as additional structure-forming agents of1-50% (relative to the material to be processed): albumins, agar-agar,gum arabic, pectins, tragacanth, xanthan, natural and modified starches,dextrans, dextrins, maltodextrin, chitosan, alginates, alginate-calciumphosphates, cellulose derivatives, polyvinyl alcohol,polyvinylpyrrolidone, polyacrylic acid and polymers of methacrylic acidand methacrylic acid esters.

Celluloseacetate phthalate or hydroxypropylmethylcellulose phthalate,azo-crosslinked polymethacrylate; polyurethane/sugar copolymers, asuitable sugar component in particular being oligomeric galactomannansor galactomannan derivatives which are then crosslinked with aliphaticdiisocyanates; galactomannan derivatives such as ethyl- oracetylgalactomannans; polysaccharides crosslinked with adipic acid,lipophilic substances such as degradable mono-, di- and triglycerides;and erodable fatty alcohols.

In a further embodiment of the invention, 1-50% strength additions ofsubstances can be selected from this group in order to suit the physicalor chemical properties of the matrix, such as e.g. the viscosity, themechanical strength or the dissolution properties of the polymericstructure, to the active compound and the intended use. Thus, forexample, using substances such as dextrans, modified starches, sugarsand in particular mannitol, pellets according to the invention can beprepared which as a lyophilizate form a highly porous network.Macromolecules such as e.g. alginates, agar-agar and pectins can be usedaccording to the invention for the additional retardation ormodification of the release of active compound.

To this groundmass can be added further auxiliaries and excipientssuitable for pharmaceutical use, such as e.g. fillers, such as e.g.lactose, dispersants, such as e.g. disodium phosphate, pH correctants,such as e.g. disodium citrate, emulsifiers, such as e.g. lecithin,stabilizers, such as e.g. ascorbic acid, cosolvents, such as e.g.polyethylene glycol, natural colorants, such as e.g. carotenoids,aromatizing substances or flavor correctants, such as e.g. sugarsubstitutes, complex-forming agents or inclusion complex-forming agents,such as e.g. cyclodextrin.

In a particular embodiment of the matrix materials or mixtures indicatedin variants A and B, which can be built up with or without addition ofplasticizer, pellets can be prepared by addition of enteric-resistantsubstances from the group: poly- and methacrylic acid derivatives,cellulose derivatives and their mixtures, which release thepharmaceutical substance only after gastric passage, i.e. that thestructure-forming agent of the matrix mixture dissolves in apredetermined pH range.

Instead of the abovementioned enteric-resistant substances, substancescan also be used which are only degraded after reaching a certainsection of the intestine by enzymes present there. These are e.g.azo-crosslinked polymethacrylates; polyurethane/sugar copolymers, asuitable sugar component in particular being oligomeric galactomannansor galactomannan derivatives which are then crosslinked with aliphaticdiisocyanates; galactomannan derivatives such as ethyl- oracetylgalactomannans; polysaccharides crosslinked with adipic acid.

Pellets according to the invention can be prepared in this manner whichare particularly suitable for colonic pharmaceutical forms. Afterreaching the colon, a pellet matrix of this type is degradedenzymatically and the incorporated pharmaceutical substance thusreleased in a controlled manner in this gastrointestinal section.

Further embodiments to colonic pharmaceutical forms are found inparticular in the international PCT application titled"Peptidarzneistoffe enthaltende Formkorper und ihre Herstellung sowiederen Verwendung" (Shaped articles containing peptide pharmaceuticalsubstances, their preparation and their use) of ALFATEC-Pharma GmbH ofthe same date.

In the case of alginate-containing basic recipes, by suspendingwater-insoluble dicalcium hydrogen phosphate (Ca₂ (HPO₄)₂ ! e.g. to givea pH-neutral to slightly basic gelatin/alginate mixture pellets can beproduced which have delayed release of the active compound. Duringgastric passage, the acidic medium dissolves the calcium salt andcrosslinks the alginate.

Furthermore, pharmaceutically acceptable hardeners, such as e.g. aldosesor citral, which after drying lead to crosslinking, can be addedaccording to the invention to the structure-forming substances derivedfrom collagen.

A suitable hardener is in particular xylose, as it makes possible aspecifically controllable crosslinking of the pellet matrix. In thismanner depot pharmaceutical forms, so-called sustained-releasepharmaceutical forms, can be realized, it being possible according tothe invention to set different release characteristics of thepharmaceutical substance with high reproducibility.

This modulation of pharmaceutical substance release is seen particularlyclearly if the behavior of a crosslinked matrix of this type is lookedat in aqueous medium. The pellets no longer dissolve in aqueous medium,on the contrary as a result of crosslinking (derivatization of thestructure-forming agent) they show a more or less highly pronouncedswelling behavior. This swelling behavior is now adjustable in acontrolled manner via the amount of crosslinking agent added, i.e. bythe extent of hardening or via the selected hardening conditions.Different molecular fractions of a structure-forming agent derived fromcollagen can in this way be crosslinked very specifically and with highreproducibility.

On the one hand, pharmaceutical substance release profiles can thus beachieved according to the invention which correspond to the conventionaldiffusion from matrix formulations (square root law, compare Higuchiequation).

On the other hand, however, which is all the more surprising, using thesame starting materials (structure-forming substances and crosslinkingagents) a pharmaceutical substance release profile of zero order (linearkinetics) can also be reproducibly established. In this special case anon-Fick's diffusion from the matrix can be assumed, i.e. aswelling-controlled diffusion with a transition from a vitreous matrixto a swollen matrix, the diffusion coefficient of the pharmaceuticalsubstance in the matrix itself gradually increasing during the swellingprocess. Intermediate states between the two release profiles shown canalso be established.

As the pellets according to the invention, as shaped articles, possesshigh mechanical stability, they can be coated with pharmaceuticallycustomary film-forming agents. The desired absorption section in thegastrointestinal tract can be specifically reached particularlyadvantageously by combination of matrix materials, which in particularhave bioadhesive properties, and film coatings (e.g. poly- andmethacrylic acid derivatives) which dissolve in defined pH ranges.

Such bioadhesive properties can be produced, for example, by partialcrosslinking of a matrix which is constructed from an auxiliary derivedfrom collagen.

Instead of Eudragits® suitable film coatings made of substances whichafter reaching the colon are degraded by enzymes present there can alsobe employed. These are e.g. azo-crosslinked polymethacrylates;polyurethane/sugar copolymers, a suitable sugar component in particularbeing oligomeric galactomannans or galactomannan derivatives which arethen crosslinked with aliphatic diisocyanates; galactomannan derivativessuch as ethyl- or acetylgalactomannans; polysaccharides crosslinked withadipic acid.

This procedure makes possible the absorption of pharmaceuticalsubstances with problematic bioavailability in a controlled manner.Furthermore, by combinations of film-forming agents, pellet mixtures canbe prepared according to the invention which release the active compoundfrom the pharmaceutical form in a pulsed manner.

The alreadymentioned bioavailability increase achievable according tothe invention is surprisingly also provided in the case of controlledcrosslinking of a pellet matrix. According to the invention, pelletpharmaceutical forms with modulated or pulsed pharmaceutical substancerelease can thus be advantageously prepared with retention of theincreased bioavailability of the pharmaceutical substance.

As is known, gelatin, depending on the preparation process, possesses anisoelectric point in the acidic (gelatin type B) or in the alkalinerange (gelatin type A). This property is utilized according to theinvention for the direct formation of micro- or nano-capsules in thematrix material. Thus, when using gelatins of opposite charge mixed withactive compound-containing solution (e.g. at a pH of 6-7), microcapsulescan be prepared by removing the solvent. When using types of gelatin orcollagen derivatives having defined molecular composition,three-dimensional crosslinkings in the nanometer range can be carriedout. Gelatins or collagen hydrolyzates can furthermore form conjugateswith the active compound e.g. with an about 2-3% strength addition ofsalts.

The bioavailability increase of pharmaceutical substances according tothe invention described at the beginning can surprisingly even beachieved if a pharmaceutical substance is present dispersed in a pelletmatrix in coarsely disperse form.

When using micronized powders which are present dispersed in a pelletmatrix according to the invention, a distinct bioavailability increaseagain results in comparison with a conventional suspension of amicronized powder. Thus, in example 8 an immediate-effect pharmaceuticalform on a pellet basis is described which contains ibuprofen. Thebioavailability of this pellet preparation compared with a conventional,orally administered suspension of micronized ibuprofen is increased byabout 100% to 150% at the same dose. Obviously, the presence of apharmaceutical substance in a preparation according to the inventionadvantageously leads to a greatly increased (more effective) absorptionof the pharmaceutical substance under physiological conditions.

Active compounds having problematic bioavailability can be broughtaccording to the invention in a further development form into a finelydisperse form promoting absorption by direct and controlledprecipitation of the active compound previously present in the matrixmaterial in dissolved form, e.g. by pH shift or removal of the solvent.

Suitable particularly finely disperse pharmaceutical substancedispersions are colloidally disperse pharmaceutical substance systems(nanosols) whose properties and preparation are described in numerouspatent applications of ALFATEC-Pharma GmbH (e.g. PCT ApplicationPCT/DE92/01010 and further PCT applications cited there).

Pharmaceutically customary organic solvents and cosolvents which arepreferably miscible in aqueous solution can be added to the claimedmatrix materials if the active compound is water-insoluble.

By the combination of pellets which contain active compounds fromdifferent indication groups, combination preparations can be obtained,eg. by filling in customary hard gelatin capsules. Useful combinationsmay be, for example:

dihydropyridine derivative+beta-sympathicolytic or diuretic.

Other intended uses are eg. filling into sachets to give beveragegranules (beverage pellets) or use for the preparation of initial dosesin depot pharmaceutical forms etc.

Starting from a single product--the shaped articles according to theinvention--a considerable technological breadth of application is thusprovided.

In the following, the process for the preparation of the pelletsaccording to the invention is described in greater detail.

Further embodiments to this are contained in the parallel international(PCT) applications listed in the following. The contents of theseparallel PCT applications, filed on the same date at the German patentoffice by the same inventors and applicants:

internal reference: P/81AL2740, Title: "Pflanzenextrakt(e) enthaltendeFormkorper, insbesondere Pellets und ihre pharmazeutische oderkosmetische Verwendung", (Shaped articles containing vegetableextract(s), in particular pellets, and their pharmaceutical or cosmeticuse), PCT/DE93/ claimed Priorities:

German patent application P 42 01 179.5 of 1.17.1992, U.S. Ser. No.07/876,876 of 4.30.1992, U.S. Ser. No. 07/876,866 of 4.30.1992 U.S. Pat.No. 5,401,502 and German patent application P 42 01 172.8.

internal reference: P/81AL2742, Title: "Verfahren zur Herstellung vonWeichgelatinekapseln nach einem Tropfverfahren", (Process for theproduction of soft gelatin capsules by a drip-feed process), PCT/DE93/claimed Priorities:

German patent application P 42 01 178.7 of 1.17.1992 and U.S. Ser. No.07/876,863 of 4.30.1992 U.S. Pat. No. 5,254,294

internal reference: P/81AL2743, Title: "Peptidarzneistoffe enthaltendePellets and ihre Herstellung sowie deren Verwendung" (Pellets containingpeptide pharmaceutical substances, their production and their use)PCT/DE93/ claimed Priorities:

German patent application P 42 01 179.5 of 1.17.1992 and U.S. Ser. No.07/876,865 of 4.30.1992 now abandoned

are hereby also made a part completely in terms of contents for thedisclosure of the present application, like the earlier PCTapplications:

PCT/DE92/01010, PCT/DE92/01012, PCT/DE92/01014, PCT/DE92/01016,PCT/DE92/01007, PCT/DE92/01008, PCT/DE92/01015, PCT/DE92/01013,PCT/DE92/01009, PCT/DE92/01011 of 12.4.1992.

In the simplest case, the process according to the invention for theproduction of active compound-containing solids can be described by thefollowing three process steps:

a) a structure-forming agent comprising hydrophilic macromolecules isdissolved in a solvent,

b) the active compound is dispersed in this solution and

c) the mixture of dissolved structure-forming agent and dispersed activecompound obtained is added dropwise to a deep-cooled inert liquefied gasand the solid is thus formed.

The first step of the process consists in dissolving the hydrophilicmacromolecule, in particular gelatin, fractionated gelatin, collagenhydrolyzates or gelatin derivatives or alternatively mixtures ofmacro-molecular substances, in a suitable solvent--water as a solvent isthe choice to be preferred in most cases. The use of heat may benecessary here, such as e.g. with gelatin a temperature of 37° C. ormore, in order to obtain a gelatin sol.

Further auxiliaries and excipients, such as e.g. fillers, such as e.g.lactose, dispersants, such as e.g. disodium hydrogen phosphate, pHcorrectants, such as e.g. disodium citrate, emulsifiers, such as e.g.lecithin, stabilizers, such as e.g. ascorbic acid, cosolvents, such ase.g. polyethylene glycol, natural colorants, such as e.g. carotenoids,aromatizing substances or flavor correctants, such as e.g. sugarsubstitutes, complex-forming agents or inclusion complex-forming agents,such as e.g. cyclodextrin are added.

Concentration ranges of the hydrophilic macromolecules, in particulargelatin, collagen hydrolyzates or gelatin derivatives are preferablybelow 30% (% by weight), e.g. in the range from 3-15%, relative to thematerial without active compound to be processed. Correspondingly thewater content of the material to be processed is up to about 70% byweight or more.

Concentration ranges of the additional structure-forming agents, suchas, for example, dextrans, sucrose, glycine, lactose,polyvinylpyrrolidone, but in particular mannitol, are below 30% (% byweight), e.g. in the range from 0-15%, relative to the material withoutactive compound to be processed. Preferably the content of additionalstructure-forming agent is not greater than the content of the actualstructure-forming agent.

As filler components, these substances, in particular mannitol, however,can improve the stability of the polymeric structure in the pelletsaccording to the invention and thus also its mechanical properties.

In the second step the dihydropyridine derivative is dispersed in asfinely divided a form as possible in the solution of the hydrophilicmacromolecule.

The system described in the second step is then added dropwise to adeep-cooled, easily evaporable liquid in the third step for shaping viaa suitable metering system, preferably in an immersion bath containingliquid nitrogen. Each discrete drop in this process assumes sphericalshape, on the one hand even during free fall, on the other hand in theimmersion bath as a result of the gas envelope formed around it or thesystem/gas interfacial tension, before complete freezing takes place.Precisely this rapid, but still controllably manageable freezing fixesthe given state of the system instantly, i.e. no pharmaceuticalsubstance can diffuse into the surrounding medium, dissolvedpharmaceutical substance can no longer crystallize out, suspensions canno longer sediment, emulsions can no longer break, thermally sensitiveor moisture-sensitive substances are cryopreserved, the excipientstructure cannot contract, etc. The preparation process using an inertliquid gas thus has no disadvantageous effect on or change in theproduct as a consequence, which is a great advantage. The desiredproperties are maintained.

In an embodiment of the process step described in a), a material capableof forming drops, mainly comprising hydrophilic macromolecules asstructure-forming agents, in particular plant proteins, plant proteinhydrolyzates, collagen, gelatin, fractionated gelatin, elastinhydrolyzates, collagen hydrolyzates, gelatin derivatives or mixtures ofthe abovementioned substances, and the active compound is prepared.

The active compound is initially dispersed, i.e. dissolved, suspended oremulsified, e.g. in the structure-forming agent present in dissolvedform, in particular plant proteins, plant protein hydrolyzates,collagen, gelatin, fractionated gelatin, gelatin derivatives, collagenhydrolyzates or elastin hydrolyzate, the nature and amount of thestructure-forming agent employed and optionally the addition of furtherauxiliaries depending on the later intended use of the shaped article.The concentration of the excipient material may vary, for example, from0.5 to 60% (g/g), preferably 0.5 to 30% (relative to the material to beprocessed). The use of heat in the temperature range from about 30° C.to 60° C., preferably about 45° C., may be necessary e.g. when usinggelatin in order to convert this into the sol form.

Addition of additional structure-forming agents of from 1-50% (relativeto the material to be processed) selected from the group consisting of:albumins, agaragar, gum arabic, pectins, tragacanth, xanthan, naturaland modified starches, dextrans, dextrins, maltodextrin, chitosan,alginates, cellulose derivatives, polyvinyl alcohol,polyvinylpyrrolidone, polyacrylic acid and polymers of methacrylic acidand methacrylic acid esters, cellulose acetate phthalate orhydroxypropylmethylcellulose phthalate, azo-crosslinkedpolymethacrylates; polyurethane/sugar copolymers, a suitable sugarcomponent in particular being oligomeric galactomannans or galactomannanderivatives which are then crosslinked in the aliphatic diisocyanates;galactomannan derivatives such as ethyl- or acetylgalactomannans;polysaccharides crosslinked with adipic acid; lipophilic substances suchas degradable mono-, di- and triglycerides; and erodable fatty alcoholscan furthermore be added to the matrix material.

In a further process variant, additions of plasticizers of from 1-50%(relative to the material to be processed) may be added selected fromthe group consisting of: glycerol, propylene glycol, polyethyleneglycols, triacetin, sorbitol, sorbitan mixtures, sorbitol solutions,glucose syrup and other polyols or sugar alcohols.

Further auxiliaries and excipients suitable for pharmaceutical use, suchas e.g. fillers, such as e.g. lactose, dispersants, such as e.g.disodium hydrogen phosphate, pH correctants, such as e.g. disodiumcitrate, emulsifiers, such as e.g. lecithin, stabilisers, such as e.g.ascorbic acid, cosolvents, such as e.g. polyethylene glycol, naturalcolorants, such as e.g. carotenoids, aromatizing substances or flavorcorrectants, such as e.g. sugar substitutes, complex-forming agents orinclusion complex-forming agents, such as e.g. cyclodextrin can be addedto this groundmass.

Of course, the mixtures according to the invention are suitable forimmediate filling in liquid form according to the process step describedin a) for shaping in containers, such as e.g. molds, soft gelatincapsules and suitable other coverings.

In one embodiment of the process step described in b), the matrixmaterial described is added dropwise for rounding (shaping) and shockdeep-freezing in an immersion bath in the range from about -70° C. toabout -270° C., preferably from about -100° C. to -220° C. Thedeep-cooled, in particular inert, liquid employed is preferably liquidnitrogen, which does not alter the constituents of the pellets. Roundshaped articles (pellets) which after drying form a mechanically stablematrix are formed in the deep-cooled liquid. Shaping is carried out bymeans of a suitable metering system. Each discrete drop in this processassumes spherical shape, on the one hand even during free fall, on theother hand in the immersion bath as a result of the gas envelope formedaround it or the system/gas interfacial tension in the immersion bath,before complete freezing takes place. Precisely this rapid, but stillcontrollably manageable freezing fixes the given state of the systeminstantly, i.e. no active compounds can diffuse into the surroundingmedium, dissolved constituents can no longer crystallize out,suspensions can no longer sediment, emulsions can no longer break,thermally sensitive or moisture-sensitive active compounds arecryopreserved, and the excipient structure cannot contract, etc. Thepreparation process using an inert liquid gas thus has nodisadvantageous effect on or change in the active compound or the matrixmaterial as a consequence. The retention of the desired properties isthus of particular advantage. Furthermore the process operates withoutsolvents, does not pollute the environment and can be carried out understerile conditions.

Suitable metering systems are all devices which can produce discrete,uniform structures, e.g. drops, of predeterminable size.

If e.g. uncontrolled drop-formation devices are used, granules areobtained; when using suitable spray or atomization nozzles with meteringpumps powders are preferably obtained as shaped articles.

Metering devices with nozzles, which eject the material to be convertedto drops at regular intervals or intermittently, can furthermore be usedfor the process according to the invention.

An additionally preferred embodiment of the process according to theinvention employs the Cryopel® process developed by Messer GriesheimGmbH (based on German Offenlegungsschrift 37 11 169). In conjunctionwith an immersion deep-freeze plant, the Cryopel® plant, the conversionof the process according to the invention to the industrial scale isparticularly simple in terms of apparatus. This plant, which can beoperated with liquid nitrogen, is particularly distinguished by itseconomy. This plant is also suitable for sterile production. Continuousoperation with low maintenance and cleaning expenditure makes possiblethe economical conversion of the process according to the invention tothe industrial scale.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows : a schematic representation in cutaway view of a devicefor carrying out the process according to the invention; and

FIG. 2 shows: a further embodiment of a device for carrying out theprocess according to the invention in schematic representation.

FIG. 3 shows: schematically the processes which take place during thepassive absorption of pharmaceutical substances in the gastrointestinalmembrane.

The Cryopel® process developed by Messer Griesheim GmbH is shownschematically in FIG. 1. The matrix solution according to the invention,which contains the active compound in dissolved, emulsified or suspendedform, is added dropwise to the liquid nitrogen bath 3 at -196° C. fromthe heatable entry device 1 via callibrated nozzles and shaped to giveround pellets with simultaneous shock deep-freezing. By means of theconveyor belt 2 running continuously over deflecting rollers, the frozenproduct is discharged via the device 5. The metering of the liquidnitrogen is carried out by means of the supply line 7 and the resultingnitrogen gas escapes via the line 6. The insulation 4 encloses theentire system.

FIG. 2 shows a schematic representation of a process in which the activecompound matrix dispersion, which is cold or heated to at most 60° C.,is added dropwise continuously via the supply line 9 by means of theheatable drop nozzles 10 in the insulated trough 11 containing liquidnitrogen 12 by means of a controllable metering pump 8. The shockdeep-frozen pellets are removed batchwise or continuously. Using thisdevice highly viscous materials can be processed.

Should the system to be processed not be sufficiently capable of flow ordrop formation, a further addition of water (e.g. of 1-10% by weight)can be carried out, the processing temperature can be increased or elseeven pressure can be used during the metering. In the converse case(system of too low viscosity), reduced pressure or temperature reductionis to be used analogously. In this manner uniform formation isguaranteed, as well as detachment of the individual drops.

The processing temperature can be varied within wide ranges, but in thecase of thermolabile active compounds should be below 50° C.

Using the metering devices described, for example, materials whoseviscosity varies within a wide range, e.g. 1×10⁻³ to 12.5 Pa×s(Pascalseconds) and higher, can thus be metered without problems.

Further deep-cooled inert liquified gases which are suitable for theprocess according to the invention can be e.g. liquid rare gases such asargon.

Depending on the metering system selected, a grain size uniformity ofover 80% can be achieved which can be even further increased byclassification.

By classification of the frozen and separated portions, these can beconverted into the liquid state once more and pelleted again so that aloss-free procedure is guaranteed.

In a preferred embodiment of the invention, the pellets are dried, twoprocess variants resulting.

Process variant A:

The shaped articles frozen at -196° C. (liquid nitrogen), e.g. pellets,are transferred to a freeze-drying plant. In this plant temperatures of15° C. below the sublimation point of water are selected with a pressureof 0.1 Pa to 10³ Pa (0.001 to 1.03 mbar). The drying operation, whichtakes place in a conventional freeze-drying plant (condenser temperature-40° C.) at -25° C. and 33 Pa (0.33 mbar) in primary drying withsublimation of the water, frozen in amorphous form by the shockdeep-freezing, from the matrix, leads after secondary drying(desorption) to a final product having a highly porous network. As aresult of the shock deep-freezing according to the invention, the wateris largely prevented from forming a crystalline phase, as a result ofwhich a solid finely disperse amorphous water phase is formed in thematrix. After the sublimation of the water present in this way, highlyporous micropore-containing networks are formed, which with respect toconventionally freezing processes have a distinctly increased surfacearea. Compared with conventionally freeze-dried materials, such pelletsare particularly easily soluble and are preferably suitable for thedevelopment of instant preparations.

Process variant B:

The frozen shaped articles, e.g. pellets, are thawed and conventionallydried. In this case it can be advantageous for accelerating the dryingprocess and for keeping to low temperatures to work under vacuum (about3,000-5,000 Pa (about 30-50 mbar)). Drying temperatures of up to 50° C.can be selected, the temperature during the drying process not risingabove 30° C. in the pellet matrix as a result of the evaporationenthalpy of the liquid.

For conventionally dried pellets (process variant B) sol/gel-formingsubstances are necessary for the matrix which, in sol form, are capableof forming drops and after cryopelleting or after thawing form a gelwhich is stable after drying. Addition of plasticizers effects thematrix material with respect to consistency. Pellets prepared in thisway are distinguished by particularly cost-effective preparation, as thelyophilization process step is not absolutely necessary.

Lipophilic active substances can be particularly advantageouslyprocessed without addition of further emulsifiers, e.g. using ultrasonichomogenizers when using types of gelatin and collagen hydrolyzates ofhigh molecular weights, before further processing to stable emulsions ormicroemulsions.

Lipophilic/oily active compounds can be e.g.: garlic oil, cod-liver oil,vitamin E and further fat-soluble vitamins, hypericon oil, lecithin,juniper oil, omega-3-fatty acids, evening primrose oil, ethereal oilsetc. With plant extracts whose active components exhibit bothhydrophilic and lipophilic properties, the lipophilic components arefirst emulsified in the matrix material and the water-solubleconstituents are dissolved in the hydrophilic matrix material and thencryopelleted.

Owing to the increased viscosity of the matrix system, active compoundspresent in suspended form can be prevented from sedimenting by simplestirring and simultaneously metered. Temperature-sensitivepharmaceutical substances are advantageously lyophilized.

The processing of the particular development forms of the inventionindicated in the dependent claims such as e.g. formulations havingcontrolled release or improved absorption, micro- and nanoencapsulation,precipitates, conjugate formation, film coatings and the preparation ofpellets having bioadhesive properties is carried out according to thegeneral sense of the description and in coordination with the particularactive compound.

The process according to the invention itself can be carried out, lookedat altogether, in a low maintenance and economical manner compared withthe prior art. The cryopelleting, which is simple to carry out per se,surprisingly makes it possible clearly to surpass the prior art.

For carrying out the process according to the invention, it issufficient in the simplest case to prepare an aqueous gelatin solutionwith a type of gelatin of the designated specification, to suspend thenifedipine or the dihydropyridine derivative homogeneously therein infinely crystalline form, and to add the system dropwise via a suitablemetering device to an immersion bath containing liquid nitrogen. Thedeep-frozen pellets formed in this way are then converted to the drystate by lyophilization.

In the context of the present invention it has advantageously been shownthat finely disperse dihydropyridine precipitates can also be produceddirectly in the gelatin solution by precipitation from a solution of thedihydropyridine in a water-miscible and pharmaceutically acceptableorganic solvent, such as e.g. alcohol. After removal of the alcohol(e.g. by evaporation), a procedure analogous to the procedure describedis used in order to prepare the shaped articles according to theinvention.

For the combination preparations already mentioned, dihydropyridinederivatives can be combined, for example, with beta-sympathicolytics ordiuretics.

In the case of optically active substances, both their racemates and theenantiomerically pure components and mixtures thereof can be employed.

Owing to the great breadth of variation of the invention, allpharmaceutical substances can be contained in the matrix materialsdescribed if they exhibit no incompatibilities with the individualconstituents of the recipe materials. The term pharmaceutical substancehere is defined according to the invention as follows:

Pharmaceutical substances can be of synthetic or natural origin, can beboth chemically homogeneous substances or substance mixtures, andcombinations of various pharmacologically active components. The termpharmaceutical substance, however, should further generally coverphytopharmaceuticals and plant extracts and finally also includehormones, vitamins and enzymes.

Enantiomerically pure active compounds or pseudoracemates are alsosuitable according to the invention.

Active compounds from the dietetic foodstuffs sector (healthcare) andfrom the cosmetic sector can furthermore be used.

In the case of pharmaceutical substances suitable for the inventionthere is no limitation with respect to the indication groups whatsoever.In the following indication groups and some associated representativesare mentioned by way of example:

1. strong analgesics, e.g. morphine, dextropropoxyphen, pentazocine,pethidine, buprenorphine;

2. antirheumatics/anti-inflammatories (NSAR), e.g. indometacin,diclofenac, naproxen, ketoprofen, ibuprofen, flurbiprofen,acetylsalicylic acid, oxicams;

3. beta-sympathicolytics, e.g. propranolol, alprenolol, atenolol,bupranolol, salbutamol;

4. steroid hormones, e.g. betamethasone, dexamethasone,methylprednisolone, ethynylestradiol, medroxyprogesterone, prednisone,prednisolone;

5. tranquillizers, e.g. oxazepam, diazepam, lorazepam;

6. alpha-sympathicolytics, e.g. ergotamine, dihydroergotamine,dihydroergotoxin;

7. hypnotics and sedatives, e.g. secbutabarbital, secobarbital,pentobarbital, doxylamine, diphenhydramine;

8. tricyclic antidepressants, e.g. imipramine, nortriptyline,clomipramine, amitryptiline;

9. neuroleptics, e.g. chlorprothixen, chlorpromazine, haloperidol,triflupromazine;

10. antigout agents, e.g. benzbromarone, allopurinol;

11. antiparkinson agents, e.g. levodopa, amantadine;

12. coronary therapeutics or calcium antagonists, e.g. nifedipine andother dihydropyridine derivatives; nitric acid esters such as glyceroltrinitrate, isosorbide mononitrate and isosorbide dinatrate; verapamil,gallopamil, molsidomine;

13. antihypertensives, e.g. clonidine, methyldopa, dihydralazine,diazoxide;

14. diuretics, e.g. mefruside, hydrochlorothiazide, furosemide,triamterene, spironolactone;

15. oral antidiabetics, e.g. tolbutamide, glibenclamide;

16. chemotherapeutics or antibiotics, e.g. penicillins such asphenoxymethylpenicillin, amoxycillin, ampicillin, pivampicillin,bacampicillin, dicloxacillin, flucloxacillin; cephalosporins such ascefalexin, cefaclor; gyrase inhibitors such as nalidixic acid,ofloxacin, norfloxacin; erythromycin, lincomycin, tetracycline,doxycycline, trimethoprim, sulfamethoxazole, chloramphenicol,rifampicin;

17. local anesthetics, e.g. benzocaine;

18. ACE inhibitors, e.g. enalapril, captopril;

19. mucolytics, e.g. acetylcysteine, ambroxole, bromhexine;

20. antiasthmatics, e.g. theophylline;

21. mineral preparations, e.g. magnesium, calcium or potassium salts,iron preparations;

22. neurotropics, e.g. piracetam;

23. ulcer therapeutics, e.g. cimetidine, pirenzepine;

24. provitamins and vitamins, e.g. biotin, cyanocobalamine,ergocalciferol, ascorbic acid, thiamine, pyridoxine, alpha-tocopherol,retinol, beta-carotene;

25. peptide pharmaceutical substances, e.g. insulin, interferons;

26. digitalis glycosides, e.g. digitoxin, digoxin;

27. antiemetics, e.g. metoclopramide;

28. enzymes, e.g. plasmin, deoxyribonuclease;

29. antiarrhythmics, e.g. prajmaline;

30. antiepileptics, e.g. phenytoin;

31. anticoagulants, e.g. phenprocoumon;

32. spasmolytics, e.g. papaverine;

33. antimycotics, e.g. clotrimazole;

34. hormones, e.g. calcitonin;

35. venotherapeutics, e.g. aescin;

36. immunosuppressants, e.g. cyclosporin;

37. tuberculostatics, e.g. rifampicin;

38. virustatics, e.g. aminoadamantane;

39. cytostatics, e.g. methotrexate;

40. vaccines, e.g. live poliomyelitis vaccine;

41. phytopharmaceuticals, e.g. Gingko biloba extract;

42. substances for the treatment of AIDS, such as e.g. reninantagonists;

43. calcium antagonists, such as dihydropyridine derivatives, inparticular nifedipine, nitrendipine or nisoldipine.

Compared with the prior art, active compounds having poor tolerabilityor problematic bioavailability, and also light-, oxidation-, hydrolysis-and temperature-sensitive substances such as e.g. poorly solublepharmaceutical substances, peptides, natural substances, enzymes,vitamins etc. can be processed particularly advantageously to givepharmaceutical forms according to the invention.

In order to explain the physiological background to the absorption ofpharmaceutical substances in general and the improved absorption ratioof the pellet formulations according to the invention adequately, aconsideration of the mechanism of the physiological absorption ofpharmaceutical substances as is also presented in appropriatepublications is initially necessary. However, the present invention isneither tied to the following attempt at a scientific explanation of thephenomena occurring according to the invention nor can it be restrictedthereby.

Passive pharmaceutical substance absorption takes place according to themodern state of knowledge (theory according to Brodie et al.), if thefollowing conditions exist:

a) the gastrointestinal membrane acts as a lipid barrier,

b) the pharmaceutical substance is only absorbed in dissolved anduncharged, i.e. nonionized form,

c) acidic pharmaceutical substances are preferably absorbed in thestomach and basic pharmaceutical substances preferably in the intestine.

After the oral uptake of a pharmaceutical substance into the body, itsabsorption, i.e. the crossing into the general circulation (biophase) ishindered to a great degree by physical barriers (see FIG. 3), namely

by the mucus layer and an aqueous layer adhering thereto

the cell membranes of the intestinal epithelial cells with theglycocalyx covalently bonded thereto and

the so-called "tight junctions" which connect the epithelial cells withone another on their apical sides.

These barriers presuppose that absorption of pharmaceutical substancestakes place through the lipid bilayers fundamentally independently oftheir distribution mechanism and state of charge (so-called passivediffusion).

The epithelial cells of the entire gastrointestinal tract are coveredwith a mucus layer which consists of mucins (glycoproteins),electrolytes, proteins and nucleic acids. In particular, theglycoproteins form with the main component of the mucus, namely water, aviscous gel structure which primarily performs protective functions forthe underlying epithelial layer. The mucus layer is bound to the apicalsurface of the epithelial cells via the glycocalyx. The glycocalyxlikewise has a glycoprotein structure which is covalently bound tocomponents of the membrane bilayer of the epithelial cells. The branchedpolysaccharides of the glycocalyx, which are either directly covalentlybonded to amphiphilic molecules of the double membrane or to proteinsincorporated in the double membrane, possess charged N-acetylneuraminicacid and sulfate radicals and are therefore negatively charged, whichcan lead to an electrostatic bond or repulsion of charged pharmaceuticalsubstance molecules or of electrostatically charged particles. Theepithelial cell membranes consist of phospholipid bilayers in whichproteins are anchored via their hydrophobic regions. The phospholipidbilayers with their lipophilic content represent a further barrier forthe transport of the pharmaceutical substances to be absorbed.

From this description, it clearly follows that charged pharmaceuticalsubstance molecules or electrostatically charged particles thereforeonly have a very low chance of being absorbed via the oraladministration route.

The shaped articles according to the invention for the first timeprovide the technical teaching to form a system with which theseabovementioned absorption barriers can be overcome.

Hydrophilic macromolecules, in particular gelatin, are amphiphilicsubstances which, depending on the pH, have differing charge states.According to the invention, the hydrophilic macromolecule in the systemsaccording to the invention can now be selected, or the pH of theformulation can be coordinated, such that a positive state of chargeresults in the physiological medium. At least a partial neutralizationof the negative surface charges of the glycocalyx can thus be achieved.This neutralization phenomenon can become increasingly effective as aresult of bioadhesive properties of the hydrophilic macromolecule, inparticular gelatin.

As dissolved pharmaceutical substance molecules can now pass through theglycocalyx unhindered without being bound or repelled by electrostaticeffects, they thus also reach the surface of the epithelial cells andare available there in a high concentration.

Active, carrier-mediated transport mechanisms or phagocytosis can nowalso make a substantial contribution to absorption.

The use of the powders, granules, or pellets according to the inventionas shaped articles can be effected e.g. by means of customary dosagesystems in hard gelatin capsules or as granules in sachets. As a resultof the good flowability and approximately round shape of the granules,good meterability can be guaranteed. When using pellets the tightestsphere packing in exact coordination of the bulk volume to the capsulesize is possible, from which an improvement in dosage accuracy in thefilling process results. Moreover, the addition of fillers can bedispensed with as a result of the appropriate selection of a certainpellet size.

The pellets having a size of 2-12 mm can be used according to theinvention for a novel single-dose buccal, nasal or oral pharmaceuticalform. Pellets employed orally are easily swallowable and can be sold inbottles with dosage dispensers in an environmentally compatible manner.In the case of buccal and nasal use, shaped article pellets withbioadhesive properties are suitable.

Powders, granules or pellets--as shaped articles--comprising matrixmaterials which dissolve rapidly and completely in cold water, can beused filled into sachets--as instant preparations for the pharmaceuticalor dietetic sector (healthcare).

Surprisingly, utilizing the bioadhesive properties of thesol/gel-forming agents, in particular gelatin, with the shaped articlesaccording to the invention buccal and nasal formulations orpharmaceutical forms having pH-controlled release can be used.

A further use of these special granules or pellets as shaped articles isprovided by their direct compressibility to give tablets. The tabletsthus obtained surprisingly show, with low friability and high breakingstrength, complete dissolution within 5 minutes, e.g. 2 minutes,measured according to customary test methods (e.g. dissolution testapparatus according to USP). Surprisingly, the good dissolvingproperties of the structural matrix are also retained after compressing.The tablets dissolve directly without advance disintegration. Incontrast to this, tablets compressed from conventional granules alwaysdisintegrate first into granule particles, which only then dissolve.

Tablet preparation from freeze-dried shaped articles according to theinvention is of importance, for example, in the design of apharmaceutical form for temperature-sensitive active compounds. Becauseof their sensitivity (e.g. heat inactivation etc.) such pharmaceuticalsubstances require particularly gentle processing processes, whichadvantageously can be very easily and simply ensured by the processaccording to the invention.

The application area for the shaped articles according to the inventionis, of course, not only restricted to pharmaceutical purposes. Areas ofuse may also be in the biotechnological sector (cryopreservation ofenzymes or bacteria, finished nutrient media in dried form etc.) and inthe cosmetics sector (processing of plant extracts such as e.g. Aloevera to give pellets offers the advantage of an ideal, drytransportation form for the moisture-sensitive extract and at the sametime the naturally synthesized matrix system is particularly suitable asa constituent for ointments and creams).

Owing to the diverse variation and combination possibilities of theshaped articles according to the invention, the release ofpharmaceutical substances in all intended uses indicated can bemodulated within wide limits.

The following examples are intended to illustrate the invention ingreater detail:

EXAMPLE 1

Pharmaceutical substance: benzocaine Recipe of the groundmass to beprocessed:

    ______________________________________    210      g of gelatin 170 Bloom    50       g of dextran (molecular weight about 10,000)    29       g of sucrose    1        g of peppermint flavoring    710      g of distilled water    1000     g    ______________________________________

The gelatin powder is mixed with the peppermint flavoring, the water,which already contains the dextran and the sucrose in dissolved form, isadded and after preliminary swelling at 50° C. the mixture is melted. 10g of micronized benzocaine are suspended in this solution withultrasonication.

The solution is then deaerated in vacuo. By means of the Cryopelmetering device it is added dropwise to an immersion bath containingliquid nitrogen and pellets are thus formed.

The shock deep-frozen, round pellet shaped articles are dried in afreeze-drying unit with primary drying at -50° C. and 5 Pa (0.05 mbar)and secondary drying at 22° C.

78% of the pellets are in the size range from 0.8-1 mm.

The dried pellets are compressed directly on an eccentric press to givea lozenge having an average benzocaine content of 5 mg.

EXAMPLE 2

Pharmaceutical substance: potassium chloride Recipe of the groundmass tobe processed:

    ______________________________________    625     g of collagen hydrolyzate (molecular weight 2,000-            3,000 D)    50      g of citric acid    2325    g of distilled water    3000    g    ______________________________________

The collagen hydrolyzate and the citric acid are dissolved in water withstirring. 190 g of potassium chloride are dissolved in this solution.

After defoaming in vacuo, the solution is added dropwise by means of theCryopel metering device to an immersion bath containing liquid nitrogenand pellets of size of on average 4 mm are thus formed.

The water is removed as in example 1 by subsequent freeze-drying.

The pellets are packaged in air-tight sachets, corresponding to anindividual dose of 1 g of potassium ions.

The contents of a sachet dissolve completely in water at roomtemperature within 30 sec.

EXAMPLE 3

Pharmaceutical substance: phenoxymethylpenicillin potassium Recipe ofthe groundmass to be processed:

200 g of dextran (molecular weight about 60,000)

200 g of collagen hydrolyzate (molecular weight 2,000-3,000)

5 g of orange flavoring

250 g of mannitol

100 g of sucrose

Distilled water to 2,500 g

The constituents are mixed and dissolved in the water. 100 g ofphenoxymethylpenicillin potassium are dissolved in this solution withstirring.

After defoaming in vacuo, the solution is added dropwise by means of theCryopel metering device to an immersion bath containing liquid nitrogenand pellets are thus formed. The water is removed by subsequentfreeze-drying.

2.31 g of the dried pellets (corresponding to an average content ofphenoxymethylpenicillin potassium of 270 mg) are used--sealed intoindividual sachets--as an instant beverage solution.

EXAMPLE 4

Example of a matrix material comprising gelatin and plasticizer, inwhich pharmaceutical substance to be processed can be dissolved.

Gelatin 150 Bloom 2.6 kg

Spray-dried sorbitol 1.0 kg

Dihydrocodeine hydrogen tartrate 0.1 kg

Water 6.3 kg

The active compound is dissolved completely in 1 kg of water withstirring. The gelatin granules are preswollen in the remaining amount ofwater and dissolved at 40° C., and sorbitol and the active compoundsolution are then added with stirring. After melting the gelatin andhomogenizing the solution, pellets as described in example 1 areprepared by dropwise addition of the material to liquid nitrogen. Thepellets are dried in the customary manner at temperatures between 20° C.and 40° C. and then filled into opaque hard gelatin capsules having anaverage content of 10 mg of dihydrocodeine tartrate. In the dissolutiontest (apparatus according to USP XXI, 500 ml of water, 37° C., 50 rpm),the pharmaceutical form releases 70% of the active compound in 4.5minutes.

The pellets obtained are transparently clear and lustrous.

EXAMPLE 5

Example of a matrix material comprising gelatin and plasticizer, inwhich the pharmaceutical substance is present in emulsified form.

Gelatin 210 Bloom 2.6 kg

Glycerol (85% strength) 1.25 kg

α-Tocopherol acetate 0.25 kg

Water 6.9 kg

The powdered gelatin is preswollen in cold water for 40 minutes and thendissolved at 50° C. Using an ultrasonic homogenizer, the active compoundis emulsified in the gelatin solution at 50° C. The oil-in-wateremulsion is then mixed with glycerol and cryopelletized. The pelletsobtained are dried as in Example 4. The pellets are metered into opaquehard gelatin capsules containing 25 mg of α-tocopherol acetate.

The pellets obtained have an opaque and lustrous appearance.

EXAMPLE 6

Example for a matrix material comprising gelatin and plasticizer, inwhich the pharmaceutical substance can be suspended.

Gelatin 250 Bloom 2.5 kg

Glycerol (85% strength) 1.0 kg

Dexamethasone, micronized powder 0.025 kg

Water 4.0 kg

The soft gelatin material is preswollen in 1 kg of water and dissolvedat 50° C. after addition of the remaining water. The active compound ishomogeneously dispersed in this solution with stirring and the solutionis then mixed with the glycerol. The suspension obtained iscryopelletized. After customary drying the pellets are filled into hardgelatin capsules having a steroid content of 0.5 mg.

The pellets obtained are transparent and lustrous.

EXAMPLE 7

Example of a single-dose pharmaceutical form.

Mixture:

0.8 kg of gelatin 250 Bloom

0.8 kg of spray-dried sorbitol

0.8 kg of acetylsalicylic acid

1.6 kg of water

The gelatin granules are preswollen for 30 minutes in the water and thendissolved at 70° C. The acetylsalicylic acid is dispersed in thesolution obtained and the sorbitol is then added.

The matrix material obtained is added dropwise to liquid nitrogen bymeans of the apparatus shown in FIG. 2 at a temperature of the nozzlesof 70° C. The shock deep-frozen pellets are classified with cooling andhave a uniform size of 8 mm.

The round shaped articles are filled into a dose dispenserand--depending on the indication--can be administered individually.

Pellets prepared in this way are palatable and increase thetolerability, in particular in the case of cardiac infarct prophylaxis.

EXAMPLE 8

Production of an ibuprofen immediate-effect pharmaceutical form based onpellets.

Demonstration of the increased bioavailability.

Recipe:

400 g of ibuprofen USP XXII, micronized powder

400 g of gelatin powder 220 Bloom

1400 g of water

The gelatin powder is preswollen for 45 min in the water and thendissolved at 60° C. The micronized ibuprofen is homogeneously dispersedin the gelatin solution and the resulting material is deaerated invacuo.

The material is added dropwise to liquid nitrogen by means of theapparatus shown in FIG. 1 and pellets are thus formed. After drying attemperatures between 20° C. and 40° C. the pellets are filled into hardgelatin capsules containing 400 mg of ibuprofen.

In an in vivo human study, the immediate-effect form described wascomparatively tested against a commercially available ibuprofenimmediate-effect formulation which contains 600 mg of ibuprofen (inmicronized form).

The following average plasma concentration-time values result, indicatedin μg of ibuprofen/ml of plasma.

    ______________________________________                 Formulation Comparison    Time (h)     from Example 8                             preparation    ______________________________________    1            27.5         5    2            35          19    2.5          37          23    3            35          22    5            17.5        15    7            8            6    9            5            5    ______________________________________

EXAMPLE 9

Production of a flurbiprofen immediate-effect pharmaceutical form basedon pellets, demonstration of the increased bioavailability.

Recipe:

50 g of flurbiprofen, micronized powder

50 g of gelatin powder 220 Bloom

175 g of water

The gelatin powder is preswollen for 45 min in the water and thendissolved at 60° C. The micronized flurbiprofen is homogeneouslydispersed in the gelatin solution and the resulting material isdeaerated in vacuo.

The material is added dropwise to liquid nitrogen by means of theapparatus shown in FIG. 1 and pellets are thus formed. After drying attemperatures between 20° C. and 40° C. the pellets are filled into hardgelatin capsules containing 50 mg of flurbiprofen.

In an in vivo human study, the immediate-effect form described wascomparatively tested against a commercially available flurbiprofenimmediate-effect formulation which contains 50 mg of flurbiprofen (inmicronized form).

The following average plasma concentration-time values result, indicatedin μg of flurbiprofen/ml of plasma.

    ______________________________________                 Formulation Comparison    Time (h)     from Example 8                             preparation    ______________________________________    0.5          6.5         2    1            8           6    2            6           4.5    3            6           3.5    5            4.5         2    ______________________________________

EXAMPLE 10

Pharmaceutical substance: nifedipine Recipe of the groundmass to beprocessed:

300 g of collagen hydrolyzate

750 g of mannitol

3950 g of distilled water

The collagen hydrolyzate and the mannitol are dissolved in the dist.water with stirring. 100 g of micronized nifedipine are homogeneouslysuspended in this solution, if desired with addition of customarypharmaceutical auxiliaries. After defoaming under vacuum, the suspensionis shaped to give pellets by dropwise addition at room temperature bymeans of the Cryopel® metering device to an immersion bath containingliquid nitrogen.

The water is removed by subsequent freeze-drying and round shapedarticles are obtained, after classification, with an average nifedipinecontent of 2 mg.

These shaped articles disintegrate completely in water at roomtemperature (dissolution test apparatus according to USP, test medium100 ml of water, 23° C.) within 20 seconds and release the amount ofnifedipine contained.

The dried shaped articles are filled into a dark-colored dose containerin which they are protected from entry of light and from which thedesired dose can be removed.

EXAMPLE 11

The dried shaped articles from Example 10 are directly compressed in aneccentric press to give tablets having an average nifedipine content of10 mg.

In a dissolution test apparutus according to USP (900 ml of 0.1N HCl,paddle, 75 rpm, 37° C.), complete. tablet dissolution and thus activecompound release results within 5 minutes.

The pellets from Example 10 can alternatively be filled into opaque hardgelatin capsules having an average nifedipine content of 5 mg.

EXAMPLE 12

The recipe of the groundmass to be processed in Example 10 is altered asfollows:

300 g of collagen hydrolyzate

60 g of polyvinylpyrrolidone K 15

100 g of sucrose

2540 g of distilled water

The further working procedure is carried out analogously to Example 10.

The examples are only exemplary embodiments of the present invention.The person skilled in the art is accordingly also free to use or toprepare all pharmaceutical, cosmetic or other shaped articles accordingto the invention such as powders, granules, essentially symmetricalaggregates etc. if required within the scope of the present invention.

We claim:
 1. A process for the preparation of powders, granules orpellets containing at least one active compound which comprises:a)dissolving a structure-forming agent comprising hydrophilicmacromolecules selected from the group consisting of: collagen, gelatin,fractionated gelatin, collagen hydrolyzates, succinylated gelatin, plantproteins, plant protein hydrolyzates, elastin hydrolyzates, in anaqueous or aqueous-organic solvent; b) dispersing the active compoundand c) adding the mixture of dissolved structure-forming agent anddispersed active compound obtained dropwise to liquid nitrogen and thusforming powders, granules or pellets, and d) drying the powders,granules or pellets thus formed by evaporation or sublimation of thesolvent in a customary manner until the solvent is removed.
 2. Theprocess as claimed in claim 1, wherein water is employed as a solvent.3. The process as claimed in claim 1 whereina) a structure-forming agentselected from the group consisting of: gelatin, fractionated gelatin,collagen hydrolyzate, succinylated gelatin and their mixtures isdissolved in a solvent, b) a dihydropyridine derivative having aneffective particle size to be dispersed in the solution, c) thedispersion of structure-forming agent and dihydropyridine derivative isadded dropwise to liquid nitrogen and powders, granules or pellets arethus formed, and d) the powders, granules or pellets thus formed aredried by evaporation or sublimation of the solvent in a customarymanner.
 4. The process as claimed in claim 1, wherein drops in anapproximately uniform predetermined shape are prepared from thedispersion by means of a metering system.
 5. The process as claimed inclaim 1, wherein the powders, granules or pellets are freeze-dried. 6.The process as claimed in claim 1, wherein the dispersion of activecompound and structure-forming agent is treated with an additionalstructure-forming agent selected from the group consisting of: albumins,agar-agar, gum arabic, pectins, tragacanth, xanthan, natural andmodified starches, dextrans, dextrins, maltodextrin, chitosan,alginates, cellulose derivatives, polyvinyl alcohol,polyvinylpyrrolidone, polyacrylic acid and polymers of methacrylic acidand methacrylic acid esters, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, azo-crosslinkedpolymethacrylate, polyurethane/sugar copolymers, galactomannanderivatives, polysaccharides, lipophilic substances, erodable fattyalcohols, and their mixtures.
 7. The process as claimed in claim 1,wherein placticizers and flavor correctants selected from the groupconsisting of:glycerol, propylene glycol, polyethylene glycol,triacetin, sorbitol, sorbitan mixtures, glucose syrup and theirmixtures, are added to the mixture of structure-forming agent and activecompound.
 8. The process as claimed in claim 1, wherein as astructure-forming agent gelatin having a maximum in the molecular weightdistribution above 10⁵ D at at most 70° C. is mixed with the activecompound.
 9. The process as claimed in claim 1, wherein the activecompound is introduced in dissolved, emulsified, suspended,microencapsulated, nanoencapsulated, microemulsified or finely disperseform or in conjugated form to the hydrophilic macromolecule.
 10. Theprocess as claimed in claim 6, wherein the sugar comprises oligomericgalactomannans or galactomannan derivatives.
 11. The process as claimedin claim 10, wherein the oligomeric galactomannans or galactomannanderivatives are crosslinked with aliphatic diisocyanates.
 12. Theprocess as claimed in claim 10, wherein galactomannan derivativescomprise ethyl- or acetyl galactomannans polysaccharides that arecrosslinked with adipic acid.
 13. The process as claimed in claim 10,wherein the polysaccharides are crosslinked with adipic acid.
 14. Theprocess as claimed in claim 10, wherein the lipophilic substancescomprise degradable mono-, di- or triglycerides.